Researchers discover what may be earliest stage of Alzheimer's disease

Older adults with elevated levels of brain-clogging plaques -- but otherwise normal cognition -- experience faster mental decline suggestive of Alzheimer's disease, according to a new study led by the Keck School of Medicine of USC that looked at 10 years of data.

Just about all researchers see amyloid plaques as a risk factor for Alzheimer's.

However, this study presents the toxic, sticky protein as part of the disease -- the earliest precursor before symptoms arise.

"To have the greatest impact on the disease, we need to intervene against amyloid, the basic molecular cause, as early as possible," said Paul Aisen, senior author of the study and director of the USC Alzheimer's Therapeutic Research Institute (ATRI) at the Keck School of Medicine. "This study is a significant step toward the idea that elevated amyloid levels are an early stage of Alzheimer's, an appropriate stage for anti-amyloid therapy."

Notably, the incubation period with elevated amyloid plaques -- the asymptomatic stage -- can last longer than the dementia stage.

"This study is trying to support the concept that the disease starts before symptoms, which lays the groundwork for conducting early interventions," said Michael Donohue, lead author of the study and an associate professor of neurology at USC ATRI.

The researchers likened amyloid plaque in the brain to cholesterol in the blood. Both are warning signs with few outward manifestations until a catastrophic event occurs. Treating the symptoms can fend off the resulting malady -- Alzheimer's or a heart attack -- the effects of which may be irreversible and too late to treat.

"We've learned that intervening before the heart attack is a much more powerful approach to treating the problem," Donohue said.

Aisen, Donohue and others hope that removing amyloid at the preclinical stage will slow the onset of Alzheimer's or even stop it.

The amyloid problem

One in three people over 65 have elevated amyloid in the brain, Aisen noted, and the study indicates that most people with elevated amyloid will progress to symptomatic Alzheimer's within 10 years.

If Alzheimer's prevalence estimates were to include this "preclinical stage" before symptoms arise, the number of those affected would more than double from the current estimate of 5.4 million Americans, the study stated.

Published in The Journal of the American Medical Association on June 13, the study uses 10 years of data from the Alzheimer's Disease Neuroimaging Initiative, an exploration of the biomarkers that presage Alzheimer's. USC ATRI is the coordinating center of this North American investigation. Aisen co-directs its clinical core.

USC plays a leading role in the only two anti-amyloid studies focused on the early, preclinical stage of sporadic Alzheimer's: The Anti-Amyloid Treatment in Asymptomatic Alzheimer's study (the A4 Study) and the EARLY Trial, Aisen said.

"We need more studies looking at people before they have Alzheimer's symptoms," Aisen said. "The reason many promising drug treatments have failed to date is because they intervened at the end-stage of the disease when it's too late. The time to intervene is when the brain is still functioning well -- when people are asymptomatic."

Although elevated amyloid is associated with subsequent cognitive decline, the study did not prove a causal relationship.

For years, researchers have acknowledged age is the biggest risk factor when it comes to Alzheimer's. For more than 90 percent of people with Alzheimer's, symptoms do not appear until after age 60, according to the Centers for Disease Control and Prevention.

In 2014, about 46 million adults living in the United States -- 15 percent of the population -- were 65 or older. By 2050, that number is expected to expand to 88 million or 22 percent of the population.

The tipping point

Researchers measured amyloid levels in 445 cognitively normal people in the United States and Canada via cerebrospinal fluid taps or positron emission tomography (PET) scans: 242 had normal amyloid levels and 202 had elevated amyloid levels. Cognitive tests were performed on the participants, who had an average age of 74.

Although the observation period lasted 10 years, each participant, on average, was observed for three years. The maximum follow-up was 10 years.

The elevated amyloid group was older and less educated. Additionally, a larger proportion of this group carried at least one copy of the ApoE4 gene, which increases the odds that someone will develop Alzheimer's.

Based on global cognition scores, at the four-year mark, 32 percent of people with elevated amyloid had developed symptoms consistent with the early stage of Alzheimer's disease. In comparison, only 15 percent of participants with normal amyloid showed a substantial decline in cognition.

Analyzing a smaller sample size at year 10, researchers noted that 88 percent of people with elevated amyloid were projected to show significant mental decline based on global cognitive tests. Comparatively, just 29 percent of people with normal amyloid showed cognitive decline.

Alzheimer's disease research worldwide

Alzheimer's was recently a disease that could be diagnosed only after death with an autopsy.

Aisen and the researchers at USC ATRI have developed ways to identify early signs of Alzheimer's by creating a set of cognitive tests called the Preclinical Alzheimer Cognitive Composite. This battery of tests and variations of it are widely used to detect Alzheimer's before dementia symptoms emerge, Aisen said.

"Our outcome measures are becoming the standard for early Alzheimer's disease intervention studies," Aisen said. "Drug companies will not invest in early intervention studies without a regulatory pathway forward. ATRI and USC are building a framework for drug development in Alzheimer's disease."

As a research institution devoted to promoting health across the life span, USC has more than 70 researchers dedicated to the prevention, treatment and potential cure of Alzheimer's disease.

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Reisa Sperling at Harvard Medical School, Ronald Petersen at the Mayo Clinic, Chung-Kai Sun at USC ATRI and Michael Weiner at the University of California, San Francisco also contributed to this study.

ABOUT THE USC ALZHEIMER'S THERAPEUTIC RESEARCH INSTITUTE

The USC Alzheimer's Therapeutic Research Institute of the Keck School of Medicine of USC is an academic institute committed to advancing the development of new treatments for Alzheimer's disease through innovative clinical trials. USC ATRI's mission to accelerate the field of AD therapeutics aligns with USC's mission to prevent, treat and find a potential cure for Alzheimer's and other neurodegenerative disorders.

Located in San Diego, the institute is a leading hub of translational and clinical research in neuroscience. ATRI works with public and private partners, including the National Institutes of Health, Alzheimer's Association, Department of Defense, pharmaceutical partners and advocacy groups to develop novel methods and to conduct innovative Alzheimer's therapeutic trials.

Since 1991, ATRI faculty and staff have worked on more than 50 Alzheimer's clinical trials and are currently involved in 14 studies, six of which are currently enrolling worldwide. Alzheimer's disease affects 1 in 3 seniors and costs $236 billion a year in health care services.

ABOUT THE KECK SCHOOL OF MEDICINE OF USC

Founded in 1885, the Keck School of Medicine of USC is among the nation's leaders in innovative patient care, scientific discovery, education, and community service. It is part of Keck Medicine of USC, the University of Southern California's medical enterprise, one of only two university-owned academic medical centers in the Los Angeles area. This includes the Keck Medical Center of USC, composed of the Keck Hospital of USC and the USC Norris Cancer Hospital. The two world-class, USC-owned hospitals are staffed by more than 500 physicians who are faculty at the Keck School. The school today has approximately 1,650 full-time faculty members and voluntary faculty of more than 2,400 physicians. These faculty direct the education of approximately 700 medical students and 1,000 students pursuing graduate and post-graduate degrees. The school trains more than 900 resident physicians in more than 50 specialty or subspecialty programs and is the largest educator of physicians practicing in Southern California. Together, the school's faculty and residents serve more than 1.5 million patients each year at Keck Hospital of USC and USC Norris Cancer Hospital, as well as USC-affiliated hospitals Children's Hospital Los Angeles and Los Angeles County + USC Medical Center. Keck School faculty also conduct research and teach at several research centers and institutes, including the USC Norris Comprehensive Cancer Center, the Zilkha Neurogenetic Institute, the Eli and Edythe Broad Center for Stem Cell Research and Regenerative Medicine at USC, the USC Cardiovascular Thoracic Institute, the USC Roski Eye Institute and the USC Institute of Urology.

In 2016, U.S. News & World Report ranked Keck School of Medicine among the Top 40 medical schools in the country.

The study used data from ADNI, which is 100 percent NIH-funded at $56 million.

Donohue is the principal investigator for two grants to develop data analysis methods for Alzheimer's, which is related to this work. One grant is Biomarkers Across Neurodegenerative Disease, which is supported by the Alzheimer's Association, Michael J Fox Foundation and Weston Brain Institute (0 percent NIH at $149,872). The second is a NIH R01 grant (100 percent NIH at $1,620,934).

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